Two monocyte-derived cytokines, Interleukin-1 (IL-1) and Interleukin-6 (IL-6); have been reported to costimulate monocyte-depleted T cell populations in the presence of mitogen, and this effect has been attributed to an accessory function of these molecules. We have now examined further the accessory function potential of IL-1 plus IL-6, and examined how these cytokines promote T cell growth with mitogen. Together, IL-1 and IL-6 additively and, to a small degree, synergistically promote the proliferation of highly purified human peripheral blood T cells with phytohemagglutinin (PHA). However, maximum costimulation by IL-1 plus IL-6 over a wide range of concentrations is significantly smaller than that induced by optimal numbers of monocytes. Also, in contrast to monocytes that costimulate equally effectively T4 positive and T8 positive cells, IL-1 plus IL-6 costimulate T4 positive lymphocytes in marked preference to T8 positive cells. IL-1 plus IL-6 induces IL-2 secretion in T cell cultures costimulated with PHA, and an antibody to the IL-2 receptor, and anti-Tac, markedly inhibits PHA-activated T cells costimulated by IL-1 plus IL6. In addition, IL-1 plus IL-6 enhance the expression of surface IL-2 receptors. Because the costimulatory effect of IL-1 plus IL-6 is quantitatively smaller than that of monocytes, and it is preferentially directed toward T4 positive as opposed to T8 positive T cells, IL-1 plus IL-6, together, appear to represent a selective set of monocyte-derived accessory signals.